Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. To date, there is still no effective antihypercholesterolemic agent commercially available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products compactin and mevinolin and a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein X is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino or acetylamino;
R' is ##STR3## wherein Q is ##STR4## R.sub.2 is hydrogen or hydroxy; R.sub.1 is hydrogen or methyl; and PA1 a, b, c and d are single bonds, one of a, b, c and d is a double bond or a and c or b and d are double bonds provided that when a is a double bond, Q is ##STR5## PA1 R.sub.4 and R.sub.5 are independently C.sub.1-3 alkyl, fluoro, bromo or chloro; and PA1 R.sub.6 is phenyl, benzyloxy, substituted phenyl or substituted benzyloxy in which the phenyl group in each case is substituted with one or more substituents selected from C.sub.1-3 alkyl, fluoro, bromo or chloro. PA1 R is selected from a group consisting of: ##STR9## wherein: m is 1 to 5; PA1 R.sup.7 is hydrogen or C.sub.1-8 alkyl; PA1 R.sup.9 and R.sup.10 independently are hydrogen, or C.sub.1-8 alkyl or when taken together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of piperidinyl, pyrrolidinyl, or morpholinyl;
The totally synthetic antihypercholesterolemic compounds are disclosed in U.S. Pat. No. 4,375,475 and have the following general structural formulae: ##STR6## wherein R" is: ##STR7## wherein: E is --CH.sub.2 --, --CH.sub.2 CH.sub.2 -- or --CH.dbd.CH--;